Safavi Kamran, Abedpoor Navid, Hajibabaie Fatemeh, Kaviani Elina
Department of Plant Biotechnology, Medicinal Plants Research Centre, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan 8155139998, Iran.
Department of Sports Physiology, Faculty of Sports Sciences, Isfahan (Khorasgan) Branch, Islamic Azad University, Isfahan 8155139998, Iran.
Biology (Basel). 2025 Mar 31;14(4):361. doi: 10.3390/biology14040361.
Diabetic cardiomyopathy (DCM), a critical complication of type 2 diabetes mellitus (T2DM), is marked by metabolic dysfunction, oxidative stress, and chronic inflammation, ultimately progressing to heart failure. This study investigated the synergistic therapeutic potential of L. (sea buckthorn, SBU) extract and metformin in a mouse model of T2DM-induced DCM. T2DM was induced using a 45% high-fat-AGEs-enriched diet, followed by treatment with SBU, metformin, or their combination. Treatment effects were monitored through bioinformatic analysis, chemoinformatic prediction, behavioral testing, biochemical assays, histopathological evaluations and gene expression profiles. Based on bioinformatic analysis, we identified key hub genes involved in the diabetic cardiomyopathy including SERPINE1, NRG1, MYH11, PTH, NR4A2, NRF2, PGC1α, GPX4, ATF1, ASCL2, NOX1, NLRP3, CCK8, COX2, CCL2, PTGS2, EGFR, and oncostatin, which are pivotal in modulating the ferroptosis pathway. Furthermore, the expression of long non-coding RNAs (lncRNAs) NEAT1 and MALAT1, critical regulators of inflammation and cell death, was effectively downregulated, correlating with decreased levels of the pro-inflammatory marker oncostatin. The combined therapy significantly improved glucose regulation, reduced systemic inflammation and protected the heart from oxidative damage. Histopathological analysis revealed notable reductions in cardiac necrosis and fibrosis. Particularly, the combination therapy of SBU and metformin demonstrated a synergistic effect, surpassing the benefits of individual treatments in preventing cardiac damage. These findings highlight the potential of integrating SBU with metformin as a novel therapeutic strategy for managing DCM by targeting both metabolic and ferroptosis-related pathways. This dual intervention opens promising avenues for future clinical applications in diabetic heart disease management, offering a comprehensive approach to mitigating the progression of DCM.
糖尿病性心肌病（DCM）是2型糖尿病（T2DM）的一种关键并发症，其特征为代谢功能障碍、氧化应激和慢性炎症，最终会发展为心力衰竭。本研究在T2DM诱导的DCM小鼠模型中探究了沙棘（SBU）提取物与二甲双胍的协同治疗潜力。采用富含45%高脂肪晚期糖基化终产物的饮食诱导T2DM，随后用SBU、二甲双胍或它们的组合进行治疗。通过生物信息学分析、化学信息学预测、行为测试、生化分析、组织病理学评估和基因表达谱监测治疗效果。基于生物信息学分析，我们鉴定出参与糖尿病性心肌病的关键枢纽基因，包括丝氨酸蛋白酶抑制剂E1（SERPINE1）、神经调节蛋白1（NRG1）、肌球蛋白重链11（MYH11）、甲状旁腺激素（PTH）、核受体亚家族4A成员2（NR4A2）、核因子E2相关因子2（NRF2）、过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）、谷胱甘肽过氧化物酶4（GPX4）、活化转录因子1（ATF1）、无翅型MMTV整合位点家族成员2（ASCL2）、NADPH氧化酶1（NOX1）、NLR家族含pyrin结构域蛋白3（NLRP3）、胆囊收缩素8（CCK8）、环氧化酶2（COX2）、趋化因子配体2（CCL2）、前列腺素内过氧化物合酶2（PTGS2）、表皮生长因子受体（EGFR）和制瘤素，这些基因在调节铁死亡途径中起关键作用。此外，炎症和细胞死亡的关键调节因子长链非编码RNA（lncRNA）NEAT1和转移相关肺腺癌转录本1（MALAT1）的表达有效下调，这与促炎标志物制瘤素水平降低相关。联合治疗显著改善了血糖调节，减轻了全身炎症，并保护心脏免受氧化损伤。组织病理学分析显示心脏坏死和纤维化明显减少。特别是，SBU与二甲双胍的联合治疗显示出协同效应，在预防心脏损伤方面优于单一治疗。这些发现突出了将SBU与二甲双胍整合作为一种新型治疗策略的潜力，该策略通过靶向代谢和铁死亡相关途径来管理DCM。这种双重干预为糖尿病性心脏病管理的未来临床应用开辟了有希望的途径，为减轻DCM的进展提供了一种全面的方法。
